THE FEMALE CYCLE EXAMINE IT TO UNDERSTAND AND PRESCRIBE
14
SUMMARY The cycle in three phases: physiology
16
Definition of the three phases of the cycle
17
The three follicular and hormonal phases
18
The hypothalamic – pituitary – ovarian axis
20
The changes in the target organs during the three phases
22
How to understand the cycle 1 . Clinical Signs Temperature
25
26
Cervical mucus
30
Cervical changes
32
Subjective signs
34
2 . Further Investigations Pelvic ultrasonography
36
Hormone levels
38
3 .The markers of ovulation
Variations in cycles during a woman’s life
42 45
Cycle length
46
Puberty
48
Post-partum et lactation
52
Post-pill
54
Pre-menopause and menopause
56
15
Clinical practice
59
Blood loss
60
White discharge
64
Hyperestrogénie relative ?????????????
66
Infertility
70
Birth control - Home tests
72
Annexes
75 « Difficult » temperature charts
76
Example Charts
77
Ordonnances type Bibliography
???????????????
78 81
16
THE CYCLE IN THREE PHASES: PHYSIOLOGY
17
THE CYCLE IN THREE PHASES : PHYSIOLOGY - DONE DÉFINITION OF THE THREE PHASES OF THE CYCLE Cycle with pregnancy (cf. cycles with fertilisation, chapter 2 – red loss 2)
Cycle without pregnancy
Implantation Period
Cervical mucus
Thermal shift
Fertile sexual intercourse
Birth
intercourse
LATENT PHASE
PERI-OVULATORY PHASE
POST OVULATORY PHASE
(approximately two weeks)
In this document, the physiology, pathology, cliniqal observation and further investigations are presented with reference only to the menstrual cycle and to its different phases. The cycle begins on the first day of menstruation and ends the day before the onset of the next one. This standard description works for all phases of the fertile life of a woman, provided slight modification is made to the limits of the cycle. To quote one example, a cycle in which pregnancy occurs ends on the day of delivery. It will have lasted a little over nine months, with the post ovulatory phase being prolonged, in the early months by the continued activity of the corpus luteum, and then by the the placenta taking over. After the delivery, as at the two extremities of a woman’s fertile life, using a definition based on the cycle will give a better understanding and interpretation of a woman’s symptoms and, if necessary, of which investigations and treatments to prescribe. The cycle will therefore be the basic unit. The three phases of the cycle: The cycle is usually described in two phases – a follicular phase beginning with the first day of menstruation and ending at ovulation – and a luteal phase stretching from ovulation to the following period. Often however the concept of a « pre-ovulatory » or « ovulatory » phase is introduced to explain the phenomenon associated with this phase. In fact it seems necessary to divide the follicular phase into two, to be able to explain what is happening with regard to the hypothalamic-pituitary-ovarian axis as well as the target organs. Therefore, in this text, the cycle will be divided into three consecutive phases ; the latent or dormant phase : from the first day of menstruation until the day before the appearance of cervical mucus at the vulva (cf. chapter on mucus) the peri-ovulatory phase: from the first day of cervical mucus being detected at the vulva until the day after ovulation the post ovulation phase: from the day after ovulation till the day before onset of next menstruation.
LATENT PHASE
PERI-OVULATORY PHASE
POST-OVULATORY PHASE (thirty seven weeks approximately
The actual limits chosen for the peri-ovulatory phase are arbitrary and can be debated without it undermining the concept of the cycle in three phases. To define the start of the peri-ovulatory phase, we have chosen to use a clinical indicator - the appearance of cervical mucus at the vulva. This was done partly from a desire to encourage clinical observation and dialogue between patient and doctor, and partly because the investigations currently used do not seem to be adequate. The fall of FSH is too gradual as is the rise of oestrogen, which can be delayed anyway. The LH surge is too late and inhibin is not yet fully understood. The changes seen with ultrasound are also too gradual and cannot be used routinely in current clinical practice. The appearance of mucus at the vulva however truly reflects what is happening in the cervix and correlates with the rise in oestrogen levels. To define the end of the fertile phase we have chosen the day after ovulation. The choice was prompted by the desire to follow as closely as possible the physiology of the cycle. For example, with regard to fertility, if one cannot guarantee that pregnancy will not result from an act of intercourse more than 7 days before ovulation in the presence of mucus, one is absolutely sure that intercourse two days after ovulation cannot result in conception (fertilisable life of the ovum is between 12 – 24 hours.) The definitions of the fertile phase used in natural methods of fertility regulation (morning of 3rd consecutive raised temperature for the Sympto-Thermal Method and 4th dry day after the mucus peak for the Billings Method) are very cautious ones designed for maximum security. It is clinically impossible at the moment to define precisely the end of the peri-ovulatory phase and so we have chosen in our examples the temperature symptom : we consider the first high temperature as corresponding to the first day of the next phase, the post ovulatory phase. (The temperature rise follows ovulation, often by two or more days: Ecochard R et al, 2001)). We could have chosen the peak mucus day + 1 or 2 days (since the peak day co-incides with +/-1 day with ovulation as determined by ultrasound in 75% of cases : Ecochard R et al, 2001) but the temperature symptom seemed more explicit since it confirms that ovulation has indeed taken place.
18
THE CYCLE IN THREE PHASES: PHYSIOLOGY-LOUISE THE THREE FOLLICULAR AND HORMONAL PHASES PHASESLHORMONALFOLLICULAIRES ET HORMONAUX Hormone hypothalamique (GnRH secreted in pulses) 100
ng/ml
30
Pituitary Hormones
FSH LH 10
15
600 500
Ovarian Hormones
pg/ml
ng/ml
10
400
estradiol
300
progestérone
5
200 100
0
0
latent period mucus température
LATENT PHASE
PERI-OVULATORY PHASE
POST OVULATORY PHASE
OUIoui Follicular development during the cycle
Cohort of follicles
Selected dominant follicule
Ovulation
Corpus Luteum
Atretic Corpus luteum
THE OVARIAN FOLLICULAR RESERVOIR: In the human female, ovarian follicles start to form in the 4th month of intra-uterine life. By the 7th month each ovary contains around 3.5 million primordial follicles, but at
19 500 birth this number has already declined to 250-500,000. By the menopause only a few dozen are left. The follicles that disappear either become atretic or enter into a growth phase leading to ovulation. Around primordial follicles begin to develop each cycle. This recruitment is independent of gonadotrophin stimulation. Within a few months, these recruited follicles become pre-antral follicles. A period of basal follicular growth which lasts 65 days and is also gonadotrophin-independent transforms the pre-antral follicles (around 0.15 mm in diameter) into antral follicles (1-2 mm in diameter). LATENT PHASE
The GnRH pulse frequency increases. FSH concentrations are high at the beginning of the cycle. LH is at basal levels and rises very slowly. Oestradiol is at basal levels but rises very slowly towards the end of the latent period. Progesterone is at basal levels. The selection of the follicle destined for ovulation takes place from the cohort of antral follicles which become available for selection in the post-ovulatory phase of the previous cycle. It is the only follicle which contains detectable levels of FSH. It will be between 5.5 and 8.2 mm in diameter. Rapid cell division takes place within the granulosa cells as a result of synergy between the FSH and local factors. The selected follicle does not produce much oestradiol at first, because the hormone activin inhibits the thecal production of androgens despite the increasing frequency of LH pulses and the upgrading of LH receptor numbers in the cell. However the situation is rapidly reversed by the synthesis of inhibin-B and follistatin which lift the inhibition of the thecal androgen production (Inhibin-B has a similar activity profile to FSH).
PERI-OVULATORY PHASE
The frequency of GnRH pulses increases considerably (to around one pulse every 70 minutes). FSH concentrations decline progressively then rise to a peak before decreasing again rapidly. LH rises more rap[idly before reaching a peak, then declines. Oestradiol rises rapidly then declines again before the LH peak. The progesterone stays at basal levels until just before ovulation when it starts to rise.
At the start of this phase: - The frequency of GnRH pulses slows to one pulse every 3 or 4 hours. - FSH is at basal levels until it rises again just before the start of the new cycle. - LH is at basal levels. - Oestradiol levels rise but never reach the levels seen in the periovulatory phase. Levels drop as menstruation approaches. - Progesterone levels are very high then drop progressively.
The selected follicle becomes dominant: “It is in the middle of the follicular phase that the chosen follicle becomes dominant (…) Only the pre-ovulatory follicle is capable of producing oestradiol levels high enough to be detected in the peripheral circulation” (Gougeon A. 2003, In press). It undergoes a preovulatory ripening process involving differentiation of the granulosa cells.
The corpus luteum (yellow body) develops from the remaining fragments of the follicle after expulsion of the oocyte. The granulosa cells become luteinised under the influence of LH and become invaded by new blood vessels. The histological distinction between granulosa cells and thecal cells becomes lost. The corpus luteum produces progesterone, 17-OH progesterone and oestradiol. A large Graafian follicle can occasionally undergo luteinisation without rupturing first, due to premature penetration of new blood vessels into the granulosa. This is known as LUF syndrome (Luteinised unruptured follicle) and can be observed in up to 4% of normal cycles (Schaison G, 1997). At the end of this phase: - The frequency of GnRH pulses starts to increase again. - FSH levels rise slightly. - LH is at basal levels. - Oestradiol drops to basal levels. - Progesterone levels fall. A cohort of 3 to 11 follicles (which entered the pre-antral phase 70 days earlier) measuring 2 to 5 mm in diameter become available for selection. These follicles become sensitive to FSH during the growth phase but they do not produce oestradiol (only low levels of androstenedione) because P450 aromatase expression is inhibited by insulin like growth factor binding proteins, endothelial growth factor and tumor growth factor alpha. If implantation does not occur, the corpus luteum undergoes involution after 11 to 16 days by apoptosis (although the factors controlling this are still littles understood). Lutolysis occurs with atresia and invasion of the corpus luteum by connective tissue. This involution and the resulting fall in serum progesterone levels trigger the onset of menstruation. If implantation should occur, the corpus luteum is maintained during the first three months of pregnancy under the influence of human chorionic gonadotrophin secreted by the implanted embryo; then its role is taken over by the placenta.
"Insulin-like growth factor II in synergy with FSH and thecal androgens induce P450 aromatase activity. Meanwhile tumor growth factor beta 1 and 2 inhibit granulosa cell proliferation and activate steroidogenesis." Inhibin B synthesis declines while that of Inhibin A increases, closely mimicking oestradiol levels. The dominant follicle develops LH receptors which allow it to continue developing despite dropping FSH levels. This follicle also produces molecules which inhibit the growth of all smaller follicles, so the other follicles within the cohort undergo regression and atresia. The dominant follicle reaches a diameter of around 20mm at the time of ovulation. After the ovulatory peak, cyclic AMP and inositol phosphate begin to be produced. They set in motion the biochemical and structural changes that will lead to ovulation: - increased blood supply to the follicle. - breach of the basal lamina. - separation of the granulosa and expansion of the cumulus cells. - transformation of folliculogenesis involving a reduction in oestradiol production and an increase in progesterone secretion. (Cholesterol is made available as a substrate once the basal lamina is breached.)
(Gougeon A, In press 2003; Young et al, 1999)
PHASE POST-OVULATOIRE
Follicle rupture is a result of several simultaneous phenomena: - a localised inflammatory reaction (appearance of leucocytes within the follicle) accompanied by cytokine and prostaglandin production. - an enzymatic digestive process resulting in weakening of the follicular structure. - contraction of the follicle allowing rupture and extrusion of the oocyte and corona radiata.
THE CYCLE IN THREE PHASES ; PHYSIOLOGIE - LOUISE
20
THE HYPOTHALAMIC-PITUITARY –OVARIAN AXIS Hormone hypothalamique (GnRH secreted in pulses)
100
ng/ml
30
FSH
Pituitary Hormones 10
LH 600
15
pg/ml
ng/ml
500
10
400
Ovarian Hormones
estradiol
300
5
200
progesterone
100
0
0
POST-OVULATORY
PERI-OVULATORY PHASE
LATENT PHASE
End
start
ENCEPHALE
Stimuli
Stimuli
GnRH
HYPOTHALAMUS
Start
Stimuli
GnRH
End
Stimuli
+
GnRH
Stimuli
GnRH
GnRH
-
-
PITUITARY
+
-
LH
FSH
FSH
LH
FSH
+ Maturation of dominant follicle
LH
FSH
LH
FSH
LH
+
ESTROGENS
+
Ripe Follicle
OVULATION
OVARY
ESTROGENS
peak
peak
+ Selection of follicle
LH
ESTROGENS
Corpus luteum
PROGESTERONE
Follicles sélectionnables
PROGESTERONE ESTROGENS
PROGESTERONE
ESTROGENS
HIGHER BRAIN CENTRE : The relay centre for an infinity of neural stimuli and co-ordinator of several different neuropeptides, the higher centres control the hypothalamic nuclei via excitatory neurotransmittors 21 (noradrenalin, serotonin) and their inhibitory counterparts (dopamine, endorphins), which accounts for the frequent disruptions to the menstrual cycle. The menstrual cycle bears true testimony to what a woman is experiencing in her life. Many disruptions to the cycle are not pathological at all but simply a reflection of life events. Communication between the patient and her doctor must therefore extend beyond the directed medical enquiry if cycle irreguliarities are to be properly understood. For example, women report prolonged cycles coinciding with foreign holidays and short or interrupted cycles associated with sudden bereavement. LATENT PHASE
PERI-OVULATORY PHASE
PHASE POST-OVULATOIRE
HYPOTHALAMUS Gonadotrophin releasing hormone (GnRH) is secreted in pulses from the ventromedial nuclei in the anterior hypophysis (median eminence) and the supra-optic nuclei.
The GnRH pulse frequency increases.
PITUITARY
FSH stimulates follicular growth and Follicle stimulating hormone (FSH) prevents apoptosis of follicular cells. and luteinising hormone (LH) are secreted in a pulsatile fashion from the anterior pituitary under the influence of GnRH*.
OVARY
Growth factors also have a regulatory role:
FSH stimulates the aromatase found within granulosa cells to transform androgens in the theca interna into oestradiol, thus allowing the differentiation process of the granulosa cells needed for them to become luteal cells. FSH stimulates the aromatase found within granulosa cells to transform androgens in the theca interna into oestradiol, thus allowing the differentiation process of the granulosa cells needed for them to become luteal cells. LH controls follicular steroidogenesis (stimulating theca interna cells to produce androgens) and initiates the cascade of events which leads to ovulation. The oestradiol produced in increasing amounts by the dominant follicle will exert negative feedback control primarily on FSH levels which will progressively drop forcing the atresia of the other follicles. When a certain threshhold is reached ,the oestradiol will trigger the LH peak, accompanied by a smaller FSH peak. This is positive feedback: GnRH secretion suddenly increases sharply and the sensitivity of gonadotrophic cells is increased. The small rise in progesterone in the pre-ovulatory phase potentialises the positive feedback of oestradiol.
Ovarian steroids exert negative feedback at two different levels: the pituitary and the hypophysis. Active secretion of LH is regulated both by progesterone and oestradiol. That of FSH is essentially controlled by oestradiol alone.
These peptides secreted by the granulosa cells and the theca interna cells will modulate or balance the action of the gonadotrophins on the ovary.
It is highest just before ovulation… …
Activin, produced by the larger pre-antral follicles and the early antral follicles, inhibit androgen production in their thecal cells. Inhibin B which is secreted by the granulosa cells of the dominant follicle, works with follistatin to stimulate thecal androgen production. Insulin-like growth factors are involved in the selection of the dominant follicle. The expression of P450 aromatase in the follicles available for selection at the end of the postovulatory phase is inhibited by IGF binding proteins, endothelial growth factor and tumor growth factor alpha.
…and drops rapidly after ovulation (as a direct result of high progesterone levels); however the pulse amplitude is greater at this time. The pulse frequency rises progressively towards the end of the post-ovulatory phase as the progesterone levels drop.
LH stimulates the corpus luteum to produce progesterone, 17-OH progesterone and oestradiol.
The progesterone slows the frequency of LH pulses.
Inhibin A, secreted by the granulosa cells of the dominant follicle once they have developed LH receptors, inhibits FSH release.
During ripening of the dominant follicle, note the role of IGF II which stimulates P450 aromatase in synergy with FSH and thecal androgens, and also the role of TGF beta 1 and beta 2, produced principally by the theca interna cells , which inhibit granulosa cell proliferation and activate steroidogenesis.
(Ferin M, 1997, Gougeon A, In press 2003, Schaison G, 1997, Young J et al, 1999)
*Alterations in the frequency and amplitude of GnRH pulses modify the circulating levels of FSH and LH: increased pulse frequency causes increases in LH levels (as in the case of polycystic ovary syndrome); a reduced frequency increases FSH levels (as in the case of anorexia nervosa)
THE CYCLE IN THREE PHASES: PHYSIOLOGY- DONE
22
CHANGES IN THE TARGET ORGANS CIBLES
Hormone hypothalamique (GnRH secreted in pulses
ng/ml
100 30
Pituitary Hormones
FSH LH 10
600
15 pg/ml
ng/ml
500
10
400
Ovarian Hormones
estradiol
progesterone
300
5
200 100
latent
0
0
mense mucus temperature
LATENT PHASE
PERI-OVULATORY PHASE
POST OVULATORY PHASE
Development of the endometrium Proliferative phase
menses
Ovulation
Secretory phase
menses
Changes in the uterine cervix and cervical mucus Cervix high, wet and open Cervix low,dryc, Tilted and hard * en microscopie électronique
Mucus, thick, white, Tight Mesh
Mucus stretchy and clear and translucent, mesh opening gradually *
Col ouvert, mou, en position haute et redressée Mucus stretchy and abundant, loose open mesh *
Cervix low, dry, tilted and hardr
Thick mucus with u tightly closed mesh*
23 LATENT PHASE
PERI-OVULATORY PHASE
POST-OVULATORY PHASE
UTERUS
Endometrium
Cervix
Cervical mucus VAGINA
The vaginal content, composed of vaginal epithelium, is the whitish coating which the blades of the speculum push back when it is introduced into the vagina. When observed through the microscope, this epithelium changes its appearance in the course of the cycle:
MAMMARY GLANDS
The abrupt drop in oestrogen and progesterone levels triggers an ischemia and a localised necrosis of the endometrium (in which prostaglandins play a major role), leading to a fragmentary and haemorrhagic desquamation of it: this is menstruation. Then the epithelium gradually rebuilds itself.
Under the effect of oestrogen, the mucus membrane thickens (from 0.5 to 5mm). The endometrial glands which at first are sparse, narrow and tubular become more sinuous. This is the proliferative phase. .
Under the effect of progesterone, the tubular cells increase in size and take on glycogen, the tubular glands become twisted and vascularization develops. The chorionic sac becomes oedemic. The endometrium is ready for possible implantation. This is the secretory phase.
The cervix opens during menstruation and then closes again. It is low, firm, dry and tilted. When touched, it has a consistency comparable to the “tip of the nose”
The cervix opens, it is high and soft. Abundant, liquid and translucent mucus is evidence of a good oestrogen secretion. When touched, it has a consistency comparable to that of the lobe of the ear.
The cervix is once more low, dry, firm and tilted. A bluish colouring is characteristic of this phase.
There is a small amount of secretion which is quite dense, does not flow, more like a mucus plug.in the cervix.
Mucus is secreted which is thick at first, then becomes more and more liquid,
The exfoliated vaginal epithelial cells are basophils and their nuclei are vesicular.
There is a mucus plug or else a thick, opaque mucus which is evidence of an oestrogen/progesterone ratio in favour of progesterone.
In response to the increase in oestradial, acidophilus cells predominate and their nuclei become pycnotic. .
The increase in progesterone brings about a decrease in eosinophiles cells and the increase in the number of leukocytes.
Oestradial is responsible for the differentiation of the galactophers and for the development of the peri-galactopher connective tissue. It causes swelling of this connective breast tissue by a muco-oedemic substance.
Progesterone acts in synergy with oestradial to bring about the transformation of the distal part of the alveoli. It is however antagonistic to oestradial at the level of the galactophoric system and the connective tissue.
The level of oestradial receptors increases under the action of the circulating oestrogens which are rising. This level of receptors reaches its maximum as ovulation approaches. Progesterone receptors are present from this phase. .
The level of oestradial receptors decreases under the action of progesterone. The progesterone receptors are dominant in this phase in the physiological situation.
(Ardaens Y et al, 1998, Lansac J et al, 2002, Schaison G, 1997)
24
25
HOW TO UNDERSTAND THE CYCLE
26
HOW TO UNDERSTAND THE CYCLE - DONE CLINICAL SIGNS: THE TEMPERATURE (1)
600
15 pg/ml
ng/ml
500 10
400
estradiol
300
Ovarian Hormones
5
200
progesterone
100 0
0
latent Mense mucus temperature
LATENT PHASE
Phase post-ovulatoire POST -OVULATORY PHASE PERI-OVULATORY PHASE 1er high reading
Basal Body Temperature
Thermal plateau nadir
Pertes rouges
Pertes rouges abondantes
TO INTERPRÉT
TO UNDERSTAND 27
Observing and charting the temperature The woman takes her temperature …: every morning, at the same time, on waking, before getting up, while fasting. If the woman has got up during the night - after one hour’s rest. always by the same route: 3 minutes rectally or vaginally with a gallium thermometer; 5 minutes in the mouth, under the tongue. with the same thermometer: there can in fact be slight variations between two different thermometers for the same temperature. … and charts the graph: Note the temperature reading, as soon as possible after taking it, on a graph with a sufficient range to be able to visualise the temperature shift. Any activity which might alter the temperature (change in lifestyle, time, illness, or medication [progestagens other than Duphaston]) should be noted so that they can be taken into account when interpreting the chart. (adap. Emperaire JC, 1995, Lansac J et al, 2002) Some criteria for reading the temperature chart have been established: the temperature shift has been defined by WHO: 3 consecutive days of temperatures at least 0.2°C higher than the temperature readings of the six preceding days. But other means of determining the shift have been proposed. This temperature shift can be abrupt or can take place over several days in successive stages (= steps) or in a saw-tooth rise (cf. temperature 2) (adap. Ecochard R et al, 2001; Gross BA, 1989; MacCarthy JJ et al, 1983; Marshall J, 1963; Royston JP, 1980) Can ovulation be pinpointed from the temperature chart? the nadir, defined as the last low reading (hypothermic) before the temperature rise is not a good indicator of the day of ovulation. Ovulation occurs within an interval between just before this nadir and the 2nd high temperature. the temperature rise cannot predict ovulation either (because it follows it, often by more than two days) but it is highly relevant in pinpointing the post-ovulatory infertile phase. -
Therefore, the temperature chart does not allow ovulation to be pinpointed but confirms that it has actually occurred. (d’après de Mouzon J et al, 1984 ; Ecochard R et al, 2001 ; Gross BA, 1989 ; Hilgers TW et al, 1980 ; Leader A et al, 1985 ; Luciano AA et al, 1990 ; Mac Carthy JJ et al, 1983 ; Moghissi KS, 1992 ; Vermesh M et al, 1987)
TO ADVISE
The temperature varies from one to two tenths of a degree from one day to the next and depending on the cycle: In the latent phase, the temperature is basal. It sometimes remains high for the first days during menstruation for reasons which are still not fully known. In the peri-ovulatory phase, oestrogens can lower the basal body temperature by one or several tenths of a degree (relative hypothermia), the lowest point being called the nadir. The temperature shift occurs at the end of the peri-ovulatory phase. In the post-ovulatory phase, progesterone raises the temperature by several tenths of a degree. Progesterone is hyperthermic,(causes the temperature to rise?) notably by means of the secretion of norepinephrine, and stabilising. 3ng/ml of progesterone is enough to produce a temperature shift whereas 10 are needed if the yellow body is to be “effective”. In the post-ovulatory phase, the thermal shift is sustained. It has been observed among some women that the temperature can drop again for one day, after one or two days at the higher level, then it rises again. This is to bring up the level of oestrogens again and is called “oestrogenic dip” (d’après Emperaire JC, 1995 ; Moghissi KS, 1992 )
TO KNOW MORE The bi-phasic appearance of the temperature chart was described for the first time by Squire in 1868 then in 1904 by Van de Velde who was the first to suggest the connection with ovulation. It was linked to the activity of the yellow body by Fruhimsholz, Rubenstein BB, et Zuck TT. After 1939 numerous studies were carried out in France, notably by Palmer R., Netter A., Geller S. Dr Van der Staapen, in Nantes, was the pioneer in its use as a means of birth control. Döring (1967), Marshall (1968), Spieler (1981) studied its significance and effectiveness.
For the doctor When there is a temperature rise which is sustained at a high level, then ovulation can be said to have occurred.
For the patient To identify the post-ovulatory infertile phase: it begins on the morning of the 3rd high, stable temperature (cf. paragraph birth control)
Numerous studies have led to the establishment of reliable criteria for interpreting the temperature chart and for studying the relationship between the development of the temperature and the time of ovulation. Women are capable of observing their temperature and their mucus whatever their culture, their (socio-)economic background and their age (Colombo B et al, 2000 ; W.H.O., 1981)
HOW TO UNDERSTAND THE CYCLE
28
CLINICAL SIGNS: THE TEMPERATURE (2)
SHORT CYCLES
A tool for diagnosis and treatment :
LONG CYCLES
Y-A-T-IL EU OVULATION ?
yes
yes
Chart 7 : cycle with a short latent phase Chart 9 : cycle with a late temperature rise (long latent phase ) chart 1 : cycle with an abrupt temperature rise
chart 2 : cycle with agradual temperature rise
NO
yes
Courbe 8 : cycle with a short postovulatory phase chart 3 : monophasic chart,then bleeding, followed by a temperature rise
Courbe 10 : cycle with long latent phase interrupted by a bleed
PREGNANCY A DEFICIENT LUTEAL PHASE – DOES IT EXIST ? IF SO, WHEN DOES TREATMENT WITH PROGESTATIF BEGIN?
CAN OVULATION BE PINPOINTED ?
yes
Chart 11 : cycle with a thermal shift of at least 17 days : this is a pregnancy Chart 4 : cycle with a shift on 15th day
Courbe 5 : cycle with an earlier shift(between 10th and 13th day)
Cycles from the same woman : it is impossible to extrapolate the expected date of ovulation from one cycle to another
latent chart 6 : cycle with a deficient lutealphase : short thermal plateau (< 12 jours) start of treatmen t(first high temperature)
cf. ordonnance 2 en annexe
menses mucus temperature bleeding
Observation at the vulva Pertes rouges
pertes rouges abondantes
First high reading haut cf.chapter on
m
TO INTERPRÉT
29
HAS OVULATION TAKEN PLACE? The presence of a shift and a sustained rise indicate the presence of a yellow body and therefore of ovulation (Graphs 1 & 2) A monophasic chart shows the absence of ovulation. This cannot, strictly speaking, be said to be a cycle. It is incomplete and the bleeding which occurs is not menstruation. Graphs 3 and 10 show cycles with a long latent phase with a temperature shift occurring after a bleed.
CAN OVULATION BE PINPOINTED? The temperature chart is not a good way of pin-pointing the peri-ovulatory phase and ovulation, even in retrospect. It cannot be used as a guide for carrying out a (Sims-) Huhner test (even with reference to the charts of preceding cycles) Indeed, the clinician cannot rely on counting back from the following menstruation since variation in cycle lengths are common and many women have irregular cycles. Besides, it must be borne in mind that when the temperature shift occurs, ovulation has often already taken place and mucus secretions have already decreased. (Graphs 4 and 5)
CYCLES LONGS/CYCLES COURTS ? The temperature chart helps the interpretation of short cycles: with a short latent phase and a temperature shift of normal length (Graph 7) with a short post-ovulatory phase (Graph 8)
-
long cycles: either with a delayed thermal shift (late ovulation) with no pathological cause (Graph 9) or without a thermal shift and pathological: these are not cycles. (Lansac J et al, 2002)
PREGNANCY? -
Pregnancy is indicated when the temperature is raised for more than 17 days. Beyond 21 days, it can be confirmed with certainty. (Chart 11) Early diagnosis of a threatened miscarriage can be made if there is a drop in temperature within the first 12 weeks of pregnancy.
AND ALSO… -
the study of non-gravid amenorrhoea: without a thermal shift, these are ovarian or sus-ovarian in origin. the study of bleeding in a young girl with absence of ovulation measuring hormonal levels can only be anticipated and interpreted according to their location in the cycle: “a hormonal assessment without a temperature chart is worthless” (Lansac J et al, 2002)
TO PRESCRIBE To help diagnosis WHAT IS THE EVIDENCE FOR A SHORT LUTEAL PHASE ? (GRAPH 6 and cf. chapter relative hyperestrogenie)
A short plateau (< 12 days) or a very gradual riset suggest an insufficient corpus luteum. (Hilgers TW et al, 1980; Lenton EA et al, 1984) the height of the rise or its level above or below 37° has no significance with regard to the quality of the corpus luteum. (Lansac J et al, 2002) NB: Even if it is normal, a temperature chart is not proof of an adequate luteal secretion since 3 ng/ml of progesterone are sufficient to cause a temperature shift whereas 10 ng/ml are necessary when speaking of correct luteal function. (Abraham GE et al, 1974; Hilgers TW et al, 1980; Moghissi KS, 1992)
The presence of indicative clinical signs and/or a doubtful temperature shift call for a progesterone assay to be done in the post-ovulatory phase.
To help treatment WHEN SHOULD TREATMENT BE STARTED ? The classic advice is to treat an insufficient corpus luteum from day 15 to day 25 of the cycle. This can have important consequences: if ovulation is delayed, beyond day 15, the effect of the progestogen will be to cause the mucus to clot and not to sustain the corpus luteum (Graph 9). Sometimes the treatment stops even before ovulation occurs (Graph 3). If ovulation is early, the treatment will be taken too late to be effective. The temperature chart allows progestogen treatment to start at the most appropriate moment: from the first high temperature. In this way, the practitioner can be sure that ovulation has really occurred.
HOW TO UNDERSTAND THE CYCLE - DONE
30
CLINICAL SIGNS : CERVICAL MUCUS
600
15 ng/ml
pg/ml
500 10
400
estradiol
300
progesterone
5
200
Ovarian Hormones
100 0
0
latent menses mucus temperature
premier point haut
Basal Temperature
peak day
Pertes rouges
Pertes rouges abondantes
Mucus at the Vulva
LATENT PHASE
PERI-OVULATORY PHASE
POST-OVULATORY PHASE
Stretchy mucus « an « elevator » for spermatozoid : it can live for several days
Mucus at the cervixet Lifespan of spermatozoa Spermatozoon trapped in the dense mucus lives one or two hours
spermatozoïd trapped in the thick mucus : it lives one or two hours
Mucus at the Vulva NO MUCUS
Mucus pasty and creamy
Stretchy Mucus very mucus stretchy and translucent
Little or no mucus
TO KNOW MORE
TO INTERPRET The practitioner observes the cervix and the mucus secretion at a precise time during an examination using a speculum. The woman observes the presence and characteristics of the mucus externally at the vulva and assesses the sensation she feels continuously throughout the cycle. (cf. ordonnance en annexe) POST-OVULATORY PERI-OVULATORY PHASE LATENT PHASE PHASE The practitioner sees a little When the oestrogen levels begin to rise, the pratitioner sees an increase in mucus, which still appears Progesterone causes an mucus on the cervix, which is white, pasty and thick. abrupt return of a scant, pasty, sticky, crumbly (not The woman can see it because this mucus appears outside at the vulva and she feels a sensation of sticky, pasty, opaque stretching at all), very thick. dampness. mucus which hardly, if at Then, as the oestrogen levels increase, the mucus is very abundant, slippery, clearer, more watery, all, descends to the vulva The woman sees nothing at the runny, stretchy (stretching several cms.), transparent. At this stage examination of a mucus sample on a vulva as this mucus does not slide reveals cystalisation in fern formation. The woman sees no more appear outside, and she has a mucus at the vulva and sensation of dryness. The Insler scale evaluates the mucus present at this phase of the cycle : feels a sensation of Score 1 2 3 dryness again The Insler scale cannot be applied Opening of the cervix pinhole Opening gaping Amount of mucus minimal A trickle A cascade (Odeblad E, 1994) Amount of stretch 1-4 cm 5-8 cm >8 cm The Insler scale registers Cristallisation Linear partial complete nothing. - between 8 and 10 the cervical secretion is good. (Insler V et al, 1972 ; Lansac J et al, 2002) - between 4 and 7, it is insufficient - between entre 0 and 3, it is non existent. The woman easily finds this mucus at the vulva, she feels a very wet sensation becoming slippery. « Peak day » is explained as the day of the most abundant, stretchy, lubricative mucus. Peak day is a good marker of ovulation (Ecochard R et al, 2001 ; Moghissi KS, 1986) This « sample » diagram has many variantes, first in the length of each phase in different women and then in accordance with the age of the women (premeopause) or certain pathological staes (infertility).
1895 : Smith describes cyclical variations of cervical 31 mucus 1933 : Seguy, Vimeux et Simonet define the relationship between mucus pattern and oestrogen levels. 1940 à 1960 : Hartman, Rubenstein, Viergilier, Pommerencke confirm the close relationship between the peak of cervical mucus and ovulation. The work of Billings et Brown (1973, 1978, 1989), Flynn et Lynch (1976), Casey (1977), Hilgers, Abraham et Cavanauch (1978), have all shown a close correlation between the woman’s observations at the vulva, changes in the cervix and the hormone levels. (except for infertility and premenopause). The work of ’Hilgers (1976) , de l’OMS (1983), de Leader (1985), de Moghissi (1986), de Nulsen (1987), de Colombo (2000), d’Ecochard (2001), who have all compared cervical mucus with other markers of ovulation, confirm that it is a good marker for pinpointing ovulation. The peak day sign is closely correlated to the time of ovulation as defined by other investigations. Since 1960, Odeblad has demonstrated the structure fibrillaire of the mucus ; Chrétien ehas produced three idimensional images of it. He and Elstein have studied itd physiological significance. The « Ovulation method » of Drs Billings has used mucus to determine the fertile and infertile phases of the cycle since 1964 and numerous natural family planning groups introduced it into their methodology.
TO UNDERSTAND WHAT IS CERVICAL MUCUS ?
NOTE : The term « white loss », currently used for discharge at the vulva, actually covers three distinct entities (cf chapter – white loss): - cervical mucus - vaginal cellular desquamation ; some women present with this desquamation, which is identical day after day. The « water test » of Micheline Quetier (Ecochard I et al, 1985) enables mucus to be distinguished from vaginal desquamation which disperses in water while mucus falls in a lump to the bottom without mixing. - pathological secretions often due to infection .
TO PRESCRIBE
TO ADVISE
To help diagnosis
Cervical mucus observation can be learnt by women in a few cycles, no matter what their age, the socio-economic status or their culture (W.H.O., 1981). cf. chapitre température. The observation procedure is simple and costs nothing.
Distinguish between physiological mucus during the cycle and pathological infection. Reassure the adolescent about the first appearance of mucus.
To help with treatment, particularly of sub-fertile couples. - Mucus observation enables the best moment to be chosen for applying the Insler scale
cycle with thermal shift on 15th day cycle with an earlier shift Consecutive cycles of a woman - the same applies to the Hühner test(the days of maximum mucus secretion).
This example shows what can happen if the Insler scale is applied to the last low reading as decided by the previous cycle. Ovulation has already taken place in this chart and there is no mucus being produced. sécrétion de glaire. Le score First high reading haut (Denis MA, 1984)
It enables: - the peri-ovulatory fertile period to be defined : a woman knows she is in her fertile period when she sees mucus externally at the vulva and when she feels a wet sensation. cf. chapter on birth regulation - sub-fertile couples to recognise their days of maximum fertility (abundant watery mucus). cf. chapter on subfertility
Cervical mucus is a hydrogel produced by the secretory glands in the endocervical crypts. The secretion of mucus is essentially under the control of hormones Oestrogen promotes its secrétion ; progesterone reduces the amount of secretion and increases its viscosity Its liquid state is composed of water, and soluble substances ( (mineral salts, sugars, lipids, amino-acids, proteins). Its solid state est glycoprotein thread which forms a net maillé de filaments.
WHAT IS THE PURPOSE OF CERVICAL MUCUS ? It is vital for the survival and storage of sperm, for neutralising vaginal acidity, for encouraging sperm migration, for protecting them d’une phagocytose intra–cervicale and for giving them capacitation. By means of its fibrousstructure, it can be : - an obstacle to migration (very tight fibres outside of the periovulatory phase ), - a medium for selection (looser fibres at the start of the phase just before ovulation ), - an « elevator » for sperm (open fibres in the ovulation phase) It has an anti-infection effect ; first by its composition (lysosyme, lactoferrine, peroxydase, and then by its physical properties (blocking the aux agents anti-infectieux by means of its fibrous structure outside the ovulatory period, and removing them in the fertile period by means of the heavy mucus flow. (Chrétien FC, 1979)
32
HOW TO UNDERSTAND THE CYCLE CLINICAL SIGNS : THE UTERINE CERVIX
First high reading Pertes rouges
Basal Temperature Pertes rouges abondantes
days
Mucus at the vulva
State of the cervix
latent menses mucus temperature
LATENT PHASE
PERI-OVULATORY PHASE
POST-OVULATORY PHASE
Cervical Observation Cervix high, soft and half open Cervix dry firm, ,tilted and closed
Cervix open, soft, high and straight
Cervix low, dry, firm, tilted and closed
TO INTERPRET
TO ADVISE 33
Le praticien notes the consistency of the cervix, its angle, and whether it is open or when touched via the vagina. In those cultures with the practice of frequently washing the vaginal area, and in some natural family planning programmes, the woman can also observe the changes in the cervix by doing cervical palpation during the cycle. PERI-OVULATORY PHASE
LATENT PHASE
Keefe has described 3 stages: They reflect the changes of the cervix during the cycle: Keefe even describes the cervix of a woman with a retroverted womb.
The cervix opens during the menses, then shuts again. Thereafter it is low, firm, dry, closed and tilted.
Cervix tilted forward
First : cervix slightly raised, softer, more slippery, half open
In the case of irregular cycles, or flat temperature charts, the cervix follows the fluctuations of oestrogen levels. Changes in the cervix indicate an oestrogenic phase and if no ovulation takes place, it returns to its characteristics of the latent phase.
POST-OVULATORY PHASE
Cervix low, firm, dry, closed and tilted.
In the post partum phase, palpation of the cervix is reliable by two months after delivery
later : cervix very high, soft, open, stright with the line of the vagina,
… then tilted backwards
Cervix returns to forward tilt
(Dispa-Limouzin C, 1989)
Le relâchement périnéal de la multipare semble laisser persister une variation de hauteur selon les phases du cycle et respecte les variations de consistances. (Keefe EF, 1977 ; Kippley JF, 1982 ; Parenteau-Carreau S, 1988 a et b)
POUR COMPRENDRE
POUR PRESCRIRE
Remarque : La hauteur du col est le reflet du ratio estrogènes/progestérone : le col s’élève lorsque le ratio est élevé. Le col s’élève et s’ouvre de façon parfois marquée au moment des règles peut être sous l’effet des prostaglandines. Un cas typique a été publié dans La pratique médicale (Ecochard R et al, 1986).
For the woman who has very little mucus at the cervix, it is still important for her to identify the peri-ovulatory phase to facilitate the tests needed in the case of subfertility. She can be encouraged to do auto-palpation of the cervix to pinpoint the peri-ovulatory period.
L’aspect du col évolue au cours de la vie de la femme : - Chez la nullipare, l’orifice externe du col est arrondi, la muqueuse endocervicale est rose, comme celle du vagin mais bien lisse et sans plis, la zone de jonction pavimento-cylindrique correspond à l’orifice externe du col. Les valves du spéculum déroulent le canal endocervical et déplacent la zone de jonction en dehors. - Pendant la grossesse, la muqueuse glandulaire est très extériorisée et le col est congestif, couleur lilas. - Après l’accouchement, l’orifice externe est légèrement ouvert transversalement, la muqueuse endocervicale est plus rouge et apparaît comme une multitude de grains arrondis après acide acétique : c’est l’ectropion. L’épithélium glandulaire va être remplacé par un épithélium malpighien soit par glissement de l’épithélium pavimenteux soit par métaplasie mais les îlots glandulaires sont toujours présent sous l’épithélium malpighien et le mucus ne pouvant plus s’échapper, il se forme des kystes glandulaires appelés œufs de Naboth.
TO KNOW MORE 8
cm
6 Height of cervix (distance vulva-cervix) 4 2
Jours du cycle
- Chez la multipare, l’orifice du col est allongé, dit « en museau de tanche ».
0
LATENT
- Lors de la ménopause, la zone de jonction remonte dans l’orifice cervical et on ne voit que la muqueuse malpighienne. Les muqueuses sont plus pâles. - Sous pilule, l’aspect ressemble à celui de la grossesse, en fonction de l’intensité des dosages du contraceptif. (d’après Lansac J et al, 2002)
10
PERIOVULATORY
20
POSTOVULATORY
32
This woman measured the height of the cervix each evening, in centimetres. The cervix is much higher in the peri-ovulatory phase. . (Ecochard I, 1987)
34
HOW TO UNDERSTAND THE CYCLE - DONE CLINICAL SIGNS: SUBJECTIVE INDICATORS
Abdominal pain
first high reading
Intermenstrual Syndrome
AP : abdominal pain
AP
LATENT PHASE
PERI-OVULATORY PHASE
AP
POST-OVULATORY PHASE
Blood loss, spotting Heavier blood loss
Pre Menstrual Syndrome
Latent phase period
AP
mucus temperature bleeding
TO ADVISE
TO INTERPRET
35
Many women experience subjective signs which are important clinical symptoms. They are considered to be patholical only when they become severe.
PERI-OVULATORY PHASE
LATENT PHASE
Inter-menstruel syndrome includes: - Pelvic discomfort, most often in the form of heaviness, sometimes quite intense, radiating up to the waist. - A bleed usually limited to a few drops of blood mixed in the cervical mucus discharge - A bloated feeling in the abdomen. It occurs around the time of ovulation. It can be accompanied by signs of congestion beyond the pelvic area, such as mastitis, headaches, irritability and lethargy. (Emperaire JC, 1995)
TO PRESCRIBE Looking at intermenstrual syndrome: - Before concluding it is functional in origin, it is necessary to check for an organic cause, especially when the occurrence is recent. - In the absence of any discernable organic cause, the symptoms are classed as functional. They are merely an exaggerated form of a physiological phenomenon. They are rarely bad enough to need treatment. (Emperaire JC, 1995) In the case of premenstrual syndrome causing time off work, progestatifs can be prescribed in the post ovulatory phase, as determined by the temperature chart. (cf. chapter on relative hyperestrogénia)
POST-OVULATORY PHASE
Pre-menstrual syndrome Its physiology is not understood but biological factors (unstable estroprogestagen levels with deficient luteal phases, fall in the level of vitamin B6, concentration of insulin on the circulating monocytes, water retention), as well as psychological and social factors, must be taken into account. The symptoms are linked together in variable strengths : Mastitis, abdominal distention, oedema of the hands and feet, headaches, nausea, irritability, depression, tiredness and aggression. It starts sometimes 10 days before the period and lasts till the end of the cycle. It affects women of all ages, independent of their parity. It can be well tolerated or on the other hand it can lead to self treatment with medication of a significant nature. (Lansac J et al, 2002)
TO UNDERSTAND
It is always interesting to locate the symptoms again in relation to the three phases of the cycle. Between normal and pathological, there is no cut off point that is easily identified; pre-menstrual syndrome which increases and becomes troublesome usually indicates relative hypo estrogenia. (Lansac J et al, 2002) (cf. chapter on relative hyperestrogénia )
With inter-menstrual syndrome, one can reassure the patient by showing from her charted symptoms how it co-incides with the estimated ovulation phase. It must be pointed out that this can be warmly welcomed as another contributory sign of ovulation from the store of indicators used for natural methods of birth regulation. (Emperaire JC, 1995)
Faced with premenstrual syndrome, it is important to reassure the patient and discuss with her possible involvement of personal problems and her surroundings. One can recommend ways to reduce of stress levels, avoid stimulants and also to take regular physical exercise. (Lansac J et al, 2002)
36
HOW TO UNDERSTAND THE CYCLE - DONE FURTHER INVESTIGATIONS : PELVIC ULTRASONOGRAPHY
Development of follicles during the cycle
Development of the endometrium latence règles glaire température
LATENT PHASE
POST-OVULATORY PHASE
PERI-OVULATORY PHASE
Ovarian ultrasonography
Rupture of a follicle caught on film Several follicles present
Selection of the follicle
ffolliclefollicle
Round follicle, the liquid drains into the cavity cavityovarienne
Formation of the corpus luteum
Corpus
Ultrasonography of the endometrium
Endometrium during the periods *d’après Ardaens Y et al, 1998
Thin endometrium
Endometrium thickening
Endometrium very thick ; enables implantation (nidation).
TO INTERPRET
TO PRESCRIRE 37
Pelvic ultrasonography, either trans-abdominal or trans-vaginal, allows the ovaries and uterus to be explored
THE LATENT PHASE
POST-OVULATORY PHASE
PERI-OVULATORY PHASE
In practice:
FOLLICULAR GROWTH AND OVULATION On the surface of the ovary a cohort of 4 to 6 small follicles will be seen, about 5 mm in diameter ; these follicles will enable the ovary to be correctly indentified in the scan
At the start of the péri-ovulatory phase, the diameter of the dominant follicle increases significantly: the cut off point is when it reaches more than 14 mm. in diameter in the scan. It increases by 2 to 3 mm a day until it reaches an undefined size at maturity (commonly around 28 mm). The other follicles gadually decline and become atretic and, at every stage of the cycle, small secondary follicles can be seen. The follicles can be seen from 3 to 5 mn. both by trans-vaginal et trans-abdominal scans. (Ardaens Y et al, 1998, Bonilla-Musoles F et al, 1989)
Indicators of Ovulation : the most sensitive and accurate indicators are: - The decrease in size of the dominant follicle, assessed by the value of its widest diameter (very rarely, the diameter continues increasing even when accompanied by other signs of ovulation, demonstrating a feature of the corpus luteaum (Ecochard R et al, 2000 ; Leader A et al, 1985 ; Marinho AO et al, 1982, Queenan JT et al, 1980)
After ovulation, the wall of the follicle thickens, the central cavity is filled with blood clots to form the corpus luteum, which is continually visible in vaginal scans. A scanning view of the corpus luteum gives no indication of its quality and therefore no diagnosis of luteal inadequacy can be made from it. (Ardaens Y et al, 1998)
- The presence of liquid in the pouch of Douglas, which becomes evident when it reachers 8 ml.or more (Ecochard R et al, 2000 ; Nichols JE et al, 1993)
In addition, there are other signs available: - The presence d’écho intrafolliculaire (described as a sign of transition of the follicle towards becoming the corpus luteum) is less sensitive and specific as the echos occur frequently before ovulation (indicationg the presence of cumulus oophorus). (Lenz S, 1985) - The irregular shape of the outline of the follicle has also been described as a sign of transition of the follicle towards the corpus luteum (Ecochard R et al, 2000) The day of ovulation can be judged as the day of the maximum size of the follicle
THE UTERUS AND ENDOMETRIUM In the menstrual phase, the abrase endometrium is hardly visible and only a double line for the uterine cavity is seen as well as clots and mucosa debris échogènes.
As the endometrium is regenerated, it appears as two bands hypoéchogènes on either side of the cavity. It grows in thickness from 4-6 mm to 10-12 mm in this phase. In the days immediately before ovulation, it develops the characteristic shape of a target or a ring around ovulation, comportant la ligne cavitaire centrale, l’endomètre hypoéchogène souligné par une ligne basale hyperéchogène. Cerical mucus appears on the scan as a liquid image the length of the endocervical canal. (Ardaens Y et al, 1998)
WHEN TO PRESCRIBE AN ULTRASOUND SCAN IN THE CYCLE? LATENT PHASE
PERI-OVULATORY PHASE
The ’endometrium continues to thicken and hyperéchogène, probablement du fait de l’aspect tortueux des glandes utérines et des sécrétions de glycogène. Just before the period,blood can be seen in the uterine cavity giving it the appearance of a pseudo-sac.
Locating the scan into the three pases of the cycle enables certain errors to be avoided, in particular: - Describing as atrophy of the endometrium when faced with an endometrium less than 4 mn thick at the beginning of the latent phase. - Describing endometrial polyps the mucosa debrisdécrire seen in scans in the menstrual phase. - Describing as ovarian dystrophy an ovary with multi follicles in the latent phase (the physiological condition of multi-follicles must not be confused with the condition of polycystic ovaries especially by vaginal scans when the micro-follicles always appear more numerous than in abdominal scans) - Describing as ovarian cycts a liquid image of less than 30 mm, in light of the fact that ripe follicles can reach that size in the peri-ovulatory phase. - Describing as hyperplasie of the endometrium a uterine cavity of little thickness in the peri or post ovulatory phase.
(Ardaens Y et al, 1998)
HOW TO ADVISE POST-OVULATORY PHASE
To assess a ovarian cyst. - to investigate de polypes muqueux hyperéchogènes de l’endomètre (l’endomètre hypoéchogène assurant un bon contraste), The endometrium gains its thick (ultrasound and doppler - Just before ovulation is the best time to see endocol polyps due to the mucus. lining and maximal échogénicity. - In the case of an inclassified bleed, seeing a homogenous muqueuse hypoéchogène along the whole length of normal cavity line will eliminate in During this phase is the best time to scan ) practical terms any anomaly of muqueuse and thus avoid rushing into a hysterosalpingogram??? icheck for fibroma sous-muqueux hypoéchogènes or malformations Without a scan : These beleedings can be recorded as: of the uterus. - atrophy of the endometrium, defined as an endometrium thickening to les than 4 mm, physiologique en ménopause non substituée, and if not, it will be most often treated by inappropriate hormones (estro-progestatif ou THS). - hyperplasie of the endometrium (due to a oestrogen stimulation without any progesterone, often resulting in anovulation) with a thickening of the endometrium, this hyperplasie simple ou glandulo-kystique (associée à une hyperéchogénicité franche et des microkystes), adénomateuse ou atypique évocatrice de cancer. A histological diagnosis is therefore indispensable (after hystéroscopie), even when the image resembles a polyp or an intracavity fibroma (Ardaens Y et al, 1998 ; Lansac J et al, 2002)
38
HOW TO UNDERSTAND THE CYCLE SIGNS TO INVESTIGATE: HORMONE LEVELS DONE
100 ng/ml 30
FSH
Pituitary Hormones
LH 10
600
15 ng/ml pg/ml
500 10
400
Ovarian Hormones
estradiol
300 5
200
progestérone
100 0
0
latent
POST-OVULATORY PHASE
LATENT PHASE
period mucus temperature
PERI-OVULATORY PHASE
TO PRESCRIRE These tests have the advantage of measuring the circulating hormone but the results reflect only a snapshot in the cycle: given the daily variations and nycthémérales in the hormone levels and their pulsatile nature, the results should only be interpreted in relation to the temperature chart (and the time of the sample for certain measurements). The technique is complex and there should be no hesitation to use a specialist laboratory. The radio-immuno et immuno-enzyme assays are the ones most used. It is necessary to double check a pathological result. A sample can be repeated three times in succession and a single measurement from these three combined sera gives a better picture of of the plasma levels. What is the best time in the cycle to presribe these tests ? « An evaluation of hormones without a temperature chart isn’t much use » (Lansac J et al, 2002).
PERI-OVULATORY PHASE
LATENT PHASE
measurement of FSH and LH measurement of prolactin measurement of testostérone plasma Tests dynamiques : - test for LH-RH - test au Clomid - test au TRH
in
estradiol assay is best done in the peri-ovulatory phase, complementing the other assays. The same applies for LH assays to monitor ovulation.
POST-OVULATORY PHASE
the measurement of progesterone levels is done in the middle of the post ovulatory phase (taking account of the fact that the progesterone graph is a une courbe en cloche, it is preferable to have samples taken if possible on days 3, 7 and 11 of the post ovulatory phase. Either an average of the three samples can be taken or else a measurement taken in the middle of the post ovulatory phase can suffice.
TO PRESCRIRE When should these investigations be presribed? FSH et LH Secondary aménorrhoea isolée cliniquement (after having excluded the diagnosis of pregnancy) Sterility with anovulation (flat temperature graph) Test for LH-RH Amenorrhoea in the context of anorexia (negative response in the acute phase with the FSH response predominant) Investigation of micropolycysticsyndrome of the ovaries Delta 4 androstènedione Hirsutism Testostérone Hirsutism Sterility with a flat temperature graph Progestérone in plasma Usually, clinical observation is sufficient to diagnose a deficient luteal phase but it must be remembered that only 3 ng are needed to achieve a thermal shift while 10 ng are needed for good luteal function. Irregular cycles with a short thermal plateau or cycles which look normal (if the plasma progesterone is above 10 ng/ml , it is physiological and requires no treatment ; if it is less than 10 ng/ml, it is indeed a deficient luteal phase ; in the case of sterility, a prolactin test should be done and in the case of obesity, a weight reducing diet should be considered and treatment with clomid could be offered. Repeated early miscarriage Prolactine Secondary amenorrhoea with or without galactorrhée Irregular cycles with short luteal phases Anovulation (flat temperature graph) Sterility with a flat temperature graph or short thermal plateau. Estradiol : This test is very rarely used as clinical observation is usually sufficientl: the existence of bleeding, either spontaneous or révélés by a test for progesterones, shows the existence of une imprégnation estrogénique notable (sans lésion organique, the endometrium can only bleed under the stimulation of estrogens) ; the absence of bleeding or periods with a negative progesterone test signifies the absence of any notable estrogen stimulation ; with pre and inter menstrual syndrome, the ratio normally shows little variation ; in all these cases, to record the levels of estradiol on a given day adds little value. The flow of mucus and changes in its appearance are good evidence of estrogen secretion (Lansac J et al, 2002 ; Emperaire JC, 1995)
TO KNOW MORE ABOUT IT
39 Different dynamic tests(Lansac J et al, 2002 ) Test for LH-RH : used for women with aménorrhoes with gonadotrophins either low or normal, to distinguish a functional and organic cause. 100 µg of LH-RH are injected intravenously to stimulate the release of Pituitary LH and FSH, which are measured at 0, 30, 45, 60 and 90 minutes. Normally, the base levels of LH rise by 4 to six 6 times and FSH by 1 or 2.times. The LH response is thus far greater than that of FSH. The response is greatest in the pre-ovulatory phase. A negative response indicates d’une pathologie hypophysaire which is either organic (adénoma), or functional. In puberty the predominant response is from FSH. Test with Clomid : this is an anti-estrogènes piyuitary inductor of ovulation which is given to a woman from 5th to 9th day of the cycle. Othe result can be judged from the temperature graph: the test is positive if there is a temperature shift and this indicates that the hypothalamic-pituitary-ovarian axix in that woman is normal; the test is negative if there is no thermal shift but does not indicate which point of the axis is disturbed, and so it is necessary to couple the test with a test for LH-RH. (Clomid acts by inhibiting the feedback mechanism of estrogens on the pituitary, which ultimately causes the rise of FSH leading to the maturation of a follicle; its use is indicated in cases of infertility from functional anovulation normoprolactinémique d’origine haute avec ovaires fonctionnels in a woman who wants to become pregnant). period mucus temperature bleeding
+ Test with Clomid
-
Tests to investigate prolactin When prolactin base levels at the start of the latent phase are hardly raised, the injection en bolus of 250 µg de TRH enablesthe possibility of hyperprolactinaemia to be defined. In a normal response the base levels of prolactin are increased 4 to 6 times. A very rapid response calls for a un traitement freinateur s’il s’y associe une infécondité d’origine ovarienne par anovulation ou dysovulation. when the prolactin base levels in the latent phase are raised (three or more times higher than normal) an exploratory test is still needed, linked with other investigations of the antepituitary. The absence of any rise in prolactin is an argument in favour of a prolactin ardenoma (most commonly cro adénome investigated by IRM). The test de freination with bromocriptin(Parlodel) consists of a treatment of half a tablet of Parlodel taken for 5 days during the evening meal, then a half tablet morning and evening with a gradual increase until 2 tablets are taken daily. After a month’s treatment, the prolactin levels should be low or more normal. (< 450 mU/l). Test with progestérone : A tablet of progestagen (for exemple Duphaston 10, which does not affect the temperature graph) is taken daily for 10 days , and followed 2 or 3 jours later by bleeding, if there is an imprégnation estrogénique préalable. This is indicated in cases of secondary amenorrhoea in the pre-menopause phase of irregular cycles and also in les retards pubertaires simples.
TO UNDERSTAND URINARY HORMONE LEVELS Despite their advantages (their simplicity, absence of variation in du nycthémère fonction) 24 hour measurement of urines samples are little used. In practice. They have been replaced by blood measurements an home test urine kits (LH). Les tests d’ovulation grand public enable the detction of the LH peak in urine, using monoclonial antibodies. The woman does it herself on an early morning urine sample from days 9 – 10 of her cycle. The colour change of the strip indicates that ovulation will place within the next 24 à 36 heures. These testers are relatively time consuming, but can be used with subfertile couples. There are 2 brands on sale in France Clearplan Ovulation Test (Polivé SNC) and Primatine (Matara). (Lansac J et al, 2002 ; Vidal, 2002)
LES MOYENS CYTO-HISTOLOGIQUES (FROTTIS ET BIOPSIE D’ENDOMETRE) These are retrospective means of defining the phase of the cycle at the time of investigation, but it gives only an rough estimate of a presise day in the cycle (Affandi MZ et al, 1985 ; Seif MW et al, 1989 ; Shoupe D et al, 1989)
HORMONE ASSAYS DONE
40
What questions to ask in caes of :
TO PRESCRIBE
ABSENCE OF PERIODS - whether it happens in a clinical context evocateur : post-partum or post-abortum ; post-pilule, following neuroleptique treatement, signs of hyperandrogénie, excessive weight loss with anorexia, context of ill health which is general or endocrinological. - If there is no conclusion reached after questioning and clinical examination, then it is advisable to: Eliminate the diagnosis of intra or extra uterine pregnancy by measuring the HCG plasma levels and by ultrsound. Investigate induced galacthorroea and measure prolactin levels.. In case of hyperprolactinaemia franche (normes x 2), look for a medical cause then conduct a test with TRH then IRM. Measure FSH et LH if all preceeding tests are normal. - LH et FSH are raised, whether it is a menopause situation or a dysgénésie gonadique without primordial follicles included, or in rare cases, ovaries resistant to gonadotrophins. A scan then a coelioscope if needed, with biopsie and a caryotype to make a diagnosis. - FSH is raised and LH is normal: is it a prei=menopause situation for which progestogen treatment can be offered to compensate for the relative hyperestrogénia - FSH is normal and LH normal or raised, look for signs of ovaires micropolycystic ovary syndrome by clinical examination (amenorrhoea preceded by long cycles hirsutism, acné, excèsweight, acanthosis nigricans of the neck or of the creux axillaires, infertility). Checking the level of delta 4 androstènedione et testosterone, an ovarian scan, even a test for LH-RH (which will accompany an explosive response of LH) can be done. Treatment with 50 mg Androcur for 20 days a month along with estrogens can be started an re-assessed after two years. For those trying to conceive, Clomid is effective in 80 % of cases. - FSH et LH are both very low, raises the fear of a hypthalamicpituitary lésion tumorale and confirming symptoms should be looked for (céphalées, visual problems…), tests dynamiques should be done and IRM en fonction du contexte. But amenorrhoea hypothalamique psychogène is common (stress, grief, travel, conjugopathie, accident…).
PUBERTY : LONG CYCLES When the periods are established before the age of 10 years and there are no abnormal clinical signs, no investigation is needed. After two years, or if clinical signs exist of hyperandrogénie, it is advisable to check : - the temperature graph - the circulating levels of FSH, LH, prolactin, testosterone, androstenedione, estradiol, and 17 OH progestérone en fin de courbe. - a pelvic scan to check the volume of the ovary and its échostructure. (cf. paragraph on puberty).
HIRSUTISM The temperature graph and measuring the levels of testostérone in the bloodwill guide the diagnosis: Regular cycles with normal temperature graphs (no biological deficiency of the luteal phase, with progesterone levels higher than 10 ng/ml in the post ovulation phase) and normal testostérone levels below 2 ng/ml : Is the hirsutism idiopathique. ? Use an anti--androgen (Androcur) linked with estrogens, or in the case of minors, an estroprogestatif. spanioménorrhée with prolonged latent phase and a modest rise of testostérone (entre 2 et 5 ng/ml) calls to mind: - perhaps polycystic ovary syndrome with raised delta 4 androstènedione due to the stimulation provoked by LH which is seems permanently elevated; FSH is normal. If the woman wants children, treatment with Clomid est available. - Perhaps a partial enzymatic block of the surrénal gland en 21 ou 11 hydroxylase, with elevation of the 17 OHprogestérone ou du désoxycortisol. The treatment is therefore restriction of androgen by Décadron or hydrocortisone which restores the androgène levels to normal and re-establishes ovulation. amenorrhoea with significant rise of testostérone (above 5 ng/ml) raises the fear of a tumour either in the ovary or the surrénalienne. Surgery is required..
PÉRI-MÉNOPAUSE AND MÉNOPAUSE Tests to confirm are generally not needed but can be useful for womem post hysterectomy in order to assess the need for supplementary treatment. The peri-ménopause is characterised at times by erratic temperature graphs with a plateau either non existent or at best, short. In the latent phase, la FSH in plasma is raised, la LH in plasma is normal; estradiol is raised in the peri-ovulatory phase; progesterone is lower than 10 ng/ml in the post ovulatory phase (and inhibin B which is détectable/ but not used in current clinical practice). In the confirmed ménopause, the temperature graph is flat, FSH is very high, LH is moderately so. estradiol is collapsed (and the level of inhibin B is not measurable ). cf. paragraphe peri-menopause and menopause
INFERTILITY First consultation: Interview of the coupe: - motivation - history of the woman (infection, cycle problems, surgical and obstetric history) and of the man (puberty, infection, surgery). Clinical examination of the couple. When the interview and examination of the couple does not lead to a diagnosis,the woman should be asked to keep a temperature chart and record her cervical mucus symptoms. Second consultation : The shape of the graph (biphasic or not) can be assessed and an Insler scale applied if the woman is in the peri-ovulatory phase.. • If the mucus is abnormal: - an infection: a course of antibiotics is recommended - very little mucus and/ or gluey : perhaps the examination has been done in the latent or post ovulatory phase (can be verified by the woman’s temperature chart) If not, treatment with estrogens (10µg of ’éthinylestradiol) or an induction of ovulation. • If the mucus is normal or has been made normal, a post coital test can be performed. It can be guided by use of a hormone treatment or it can be done on the day the woman sees very fertile type mucus. The post coital test facilitates the examination of spermatozoa within the context of the vagina and cervix. Normally 5 à 10 mobile spermatozoa should be seen per grid (x400) in the endocol, about 8 à 16 heures after coitus which was preceded by 3 days abstinence. If the post coital test is abnormal, a spermocytogramme.should be asfed for. • If the temperature graph is flat, FSH, LH, prolactin levels and testostérone levels in plasma should be tested. - FSH normal, LH raised, testostérone slightly raised : evokes polycystic ovary syndrome to be treated with Clomid. - FSH and LH both raised : évokes an ovarian cause, determined by an ultrasound scan and if necessary, coelioscope with biopsie and a caryotype. For premature menopause or dysgénésie gonadique, the couple are infertile. Their choices can be discussed : do nothing ; adopt or look for donor eggs - FSH et LH very low : évokest a cause in the upper hypothalamus and pituitary, to be determined by a test for LH-RH, use of Clomid, IRM of l’hypothalamo-hypophyse. - prolactin raised : an etiologic assessment should be made - a deficient luteal phase (a short thermal plateau or normal but with progestéronémie lower than 10 mg in the mid point of the post ovulory phase). This can be treated with ovulation induction • If the temperature graph is normal, as well as the progestéronémie in the post-ovulatory phase, the mucus and the post coital test, then the patency of the fallopian tubes should be checked by hystérosalpingogram (Lansac J et al, 2002) (Emperaire JC, 1995 ; Lansac J et al, 2002 )
41
HOW TO UNDERSTAND THE CYCLE
42
THE MARKERS OF OVULATION - DONE 100
Pituitary Hormones
ng/ml
30
FSH 10
LH 15
600 500
Ovarian Hormones
ng/ml
pg/ml
10
400
estradiol
300 5
200
progestérone
100 0
0
latent
PERI-OVULATORY PHASE
LATENT PHASE
POST-OVULATORY PHASE
jour de l’ovulation peak dayt : urinary levels :
scans :
maximum secretion of mucus FSH peak Peak of d’estrone-3-glucuronide LH peak day of maximum growth of follicle
Scan of a follicle before ovulation with cumulus Ecochard R et al, 2001
A few minutes later, the ruptured follicle triangular shape and liquid flowing out into the ovarian fossette
Confirmation of’ovulation by the rise in température
period mucus température
TO ADVISE
TO INTERPRÉT
43
STUDYING THE SIGNS DURING THE PÉRI-OVULATORY PHASE
Indirect Signs Classically, the plasma peak of LH serves as a reference for pinpointing ovulation : « A definite increase in the concentration of circulating LH is the best parameter for detecting ovulation » wrote the WHO team in 1980 in an article showing that for 107 women, the day of ovulation had been determined by laparotomy and conformed with plasma levels LH, FSH, P et E2. The urinary levels of LH have proved to be as reliable as those of plasma LH : « The urinary tests for LH levels have a good correlation with the peak LH in plasma and predict ovulation for all patients » (Luciano et al, 1990), after comparing blood levels of E, P et LH, the urinary levels of LH, ultrasound scans, the température and mucus mucus over 50 cycles. But these levels are subject to biological variations (Garcia JE et al, 1981).
In daily medical practice, observation of the fluid mucus at the vulva, confirmed by the use of urinary test kits for détecting LH, enables the approach of ovulation to be defined very precisely. It is a strategy particularly useful for dealing with subfertility.
Direct Signs Although less accurate than laparoscopy, and available in current practice, ultrasound scanning is the only direct means of of proving ovulation (Luciano AA et al, 1990 ; Marinho AO et al, 1982 ; Queenan JT et al, 1980 ; Shoupe D et al, 1989 ; Vermesh M et al, 1987). It has been suggested as the reference marker for ovulation (Moghissi KS, 1992) but allowing for the average techniques and constraints which it it imposes, it cannot be used for this purpose daily. However it does represent a valuable support in the scene of infertility dans le cadre de l’hypofertilité (the constraints being more easily accepted).
Comparison (Ecochard R et al, 2001) If these two indices are compared (LH peak and ultrasongraphy), it is found that : - on average, the urinary peak of LH follows the day of ovulation as seen by ultrasound (on average by 0.46 jour). But there are premature peaks of LH, often in long cycles (10%) and some late peaks (20%) : the LH which had begun to rise before the day of ovulation by ultrasound continued its rise after it. - the start of the LH surge has shown itself to bec loser to ovulation than the peak itself. (Kesner JS et al, 1998 ; Singh M et al, 1984).
TO PRESCRIRE The good markers to use: -
the peak day of the mucus secretion LH levels ultrasound
In pratice, the coupling of these two factors, (LH peak and ultrasound) offer a secure strategy for the prediction of ovulation in 90% of cycles, including long cycles, which is interesting in practice since the test strip for LH is cheap and easily performed at home. These two indices have equally been compared with: other urinary hormone levels: - the peaks of FSH andestrone-3-glucuronide co-incide with the day of ovulation, - the peak of pregnanediol-3α-glucuronide is too slow to predict ovulation but id interesting for identifying the infertile phase post-ovulation, - the rapid rise of the ratio estrone-3-glucuronide/pregnanediol-3α-glucuronide seems reliable for 75% of cycles (this ratio is not dependent on urinary dilution and so it must be adjusted with la clairance de la créatinine (Baird DD et al, 1995)), - in pratice, the urinary tests for pregnanediol-3α-glucuronide, d’estrone-3-glucuronide and FSH are still more expensive and less easily available as home test kits than the LH kit. The need to resort to a laboratory restricts their use to programmes of assisted reproduction. Examination of mucus and body temperature: - The temperature rise does not help to predict ovulation but it does confirm the event. - the mucus peak, on the other hand, has proved to be an excellent sign: in 75% of cycles, the peak day corresponds to +/- 1 day near or on the day of ovulation as détermined by ultrasound in this study (agreeing with the figures of Baird DD et al, 1991 ; Hilgers TW et al, 1978, Leader A et al, 1985). In pratice, the zero cost, the simplicity, the auto-identification of the mucus and the température symptoms makes them as valuable in family planning as in subfertility.
TO KNOW MORE Ecochard R et al, 2001. This study, of 326 cycles of 107 femmes, looked at : - urinary measurement of LH, FSH, estrone-3-glucuronide, pregnanediol-3α-glucuronide - variations in body temperature and cervical mucus - ovarian scans The aim was to compare the days of ovulation determined by the LH peak, ultrasound and other indices. It showed that the mucus peak, the ratio of urinary métabolites and the start of the LH surge proved to be the better markers of ovulation than the LH peak
44
45
VARIATIONS IN CYCLES DURING A WOMAN’S LIFE
46
VARIATIONS IN CYCLES DURING A WOMAN’ LIFE CYCLE LENGTH - DONE
latence règles glaire température
PERI-OVULATORY PHASE
LATENT PHASE
POST-OVULATORY PHASE
È
OVULATION OCCURRED ON 14 DAY IN ONLY 18% OF CYCLES
Probably spontaneous miscarriages 5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
5
6
7
8
9
1 0
Length of the follicular phase (days) (length of the latent phase + the péri-ovulatory phase)
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
Durée de la phase lutéale (jours) (durée de la phase post-ovulatoire)
More than 25% of cycles have a follicular phase < 14 jours Aproximately 56% have a follicular phase >14 jours
About 50% of cycles have a post-ovulatory phase < 14 jours About 20% have a post-ovulatory phase between 15 and 16 jours inclusive
THE CYCLE DOES NOT ALWAYS LAST 28 JOURS
38% of cycles are less than 28 jours in length 44% of cycles are more than 28 jours in length
Données de l’étude de l’OMS, 1983
≤ 22
23
24
25 26
27
28 29
30
31
32 33
34
35
36 and more
days
HOW TO INTERPRET In the great majority of cases, it is the length of the latent phase which varies. The length of the other phases has less variation. Colombo, in a study of 6724 cycles, estimates a coefficient of variation of 25.7% in the length of the pre-ovulatory phase. This is significantly more important than that of the post-ovulatory phase (16.2%). LATENT PHASE PERI-OVULATORY PHASE POST-OVULATORY PHASE cf. graph 7 chap. temp. 2
- Short, oe even in exceptional cases, absent, when ovulation is already in preparation from the beginning of the period. In this case, the peri-ovulatory phase begins either during the period or immediately after it. Thes short cycles are common in the périménopause. - Long, lasting anything from several weeks to several months ; these long cycles are frequent post-partum, post-pill, en périménopause and also at times of stress There are three types of long cycles: - Cycles with a long latent phase, with the ova continually resting
The length of the periovulatory phase is relatively unchanging ; it is conditioned by the time necessary for the selected follicle to ripen and become capable of ovulating.
The post ovulatory phase does not last longer than 16 days if there is no fertilisation. It can be short, especially post partum, post pill, or towrds the menopause.
cf. graph 9 chap. temp. 2
- Cycles with a latent phase interrupted one or more times by unsuccessful attempts at ovulation, by a simple fluctuation in the oestrogen levels or by the ripening of a follicle which doesn’t seem to « go anywhere », stopping for an unknown reason or blocked by stress or some other event. These cycles are recognised by repeated episodes of mucus interspersed with periods of dryness. cf. graph 5 chap. blood loss 1
These episodes of mucus are sometimes followed by bleeding which accompanies a sharp drop in oestrogen levels.
latent menses mucus temperature bleeding
cf. courbe10 chapitre température 2
Note that sometimes ovulation is brought on early by stress, but before this ovulation, there is always a time of preparation, with maturation of the follicle and secretion of clear fertile mucus. More often, stress interrupts follicular growth and a bleeding occurs before the expected date of the following period.
(d’après Colombo B, 2000 ; Ecochard R, 1982 ; W.H.O., 1983)
ADVICE TO GIVER A woman whose cycles are very irregular can be advised to note her own observations on a chart Interpretation will make it possible to understand the phenomena and to distinguish between the bleeding at the end of cycles which are naturally irregular, and intermittent bleeding which might be mistaken for true menstruation. .
TO PRESCRIBE Should one treat irregular cycles? If they are not accompanied by untoward symptoms, it is not necessary to regularise them. This is particularly true during adolescence.
POUR EN SAVOIR PLUS 47 WHO in 1983 studied 7514 cycles of 869 femmes with respect to different parameters : length of cycle, recognition of peak day of maximum mucus secretion (considered as a marker of ovulation and accepted as a a good one) and the definition of the fertile period (beginning at the first appearance of mucus or a sensations of dampness, and finishing three days after the peak day). In this study, the follicular phase is defined as lasting from the first day of menstruation until the peak day inclusive, and the luteal phase from peak day +1 until the end of the cycle. Out of the 7514 cycles, 6472 were considered normal and included in the sample. (the cycles eliminated: pregnancies (130), cycles in which peak day could not be clearly demonstrated (200), cycles in which there were several episodes of mucus separated by several dry days (702), cycles of women who recorded observations in only that one cycle. Note that the exclusion of 702 cycles in which episodes of mucus were separated by several dry days represents a bias, for those cycles in which there had been unsuccessful attempts at ovulation were immediately eliminated. This study showed: - the variability of cycle length as well as the length of the different phases of the cycle (cf diagram above); - variations in cycle-length to be less significant in the individual woman than from woman to woman. In order to compare cycle-length in respect of age, women were divided into 4 age-groups: 18-22; 23-27; 28-32; 33-39; The average cycle length of the four groups was respectively 29.2, 29, 28.6, 27.9 days: there is no significant difference between women of less than 23 years and those in the 23 – 27 years age-group; but all the other differences are significant, and the tendency for cycle to shorten with age is also significant. LENTON in 1984 in a study of 293 cycles from women of 19 – 39 years, looked at: – the length of the follicular phase, calculated from the first day of menstruation until the plasmatic peak of LH (not included) and its variation according to age; – the length of the luteal phase, calculated from the plasmatic peak of LH (not included) the last day before the following menstruation, and its variation according to age. She deduced that cycles in which the luteal phase is of 12 – 17 days (inclusive) can be considered normal, with an average of 14.13 days. On the other hand, the following were considered abnormal (using statistical methods): all cycles with a luteal phase of 9 days or less, as well as 74% of those cycles in which the luteal phase lasts 10 days, 22% of those lasting 11 days and 2% of those lasting 12 days. The total incidence of short luteal phases was estimated at 5.2%, and was more significant in the younger (18-35) and the older (40-44) age groups.
VARIATIONS IN CYCLES DURING A WOMAN’S LIFE
48
PUBERTY - DONE
By simple observation we can look at the onset of puberty, which can be divided into three phases: these follow one another in a variable space of time. 1. Episodes of mucus not followed by bleeding . latence
2 Appearance of bleeding: the menarche These episodes are sometimes 'break-through' bleeding, and can be repeated for months, if not years.
règles glaire température saignements
3. Gradual establishment of ovulation, with a corpus luteum at first short-lived, but gradually lasting long enough to permit implantation. Some girls have this ovulation very early, as is evidenced by precocious pregnancies.
These ovulations can be preceded by fruitless attempts at ovulation, alternating with menstrual periods. For example, here are the observations of 2 cycles of a young woman of 17 years. They show evidence of long, repeated periods of high oestrogen, gaps which are difficult to recognise and short plateaux. These irregularities will generally correct themselves naturally in the next few years. If this does not happen, further investigations should be carried out.
first high reading
Red loss
Heavy red loss
Temp. Rise around 25th day only 1.5 tenths od a degree
Bleeding on 11th and 12th days; bleeding again from 22nd to 26th day ; And perhaps a thermal shift on 36th day….
49
TO UNDERSTAND DONE The average age of menarche (establishment of menstruation) is about 13 years in France, and the first menstrual periods generally occur 2 to 3 years after the development of secondary sexual characteristics (pubic hair and mammary glands). The maturation of the hypothalamic-pituitary-ovarian axis is often not reached until two years after the establishment of the first periods, and the first "cycles" of the adolescent girl are often anovulatory. The latent phase of the cycle is in fact interrupted by an unsuccessful attempt at ovulation: the raised level of oestrogens causes a thickening of the endometrium but in the absence of ovulation the level of oestrogens returns to its base point and the endometrium, "deprived of hormones", comes away and causes a blood-loss. This "attempt at ovulation" will be followed by another fruitless attempt, again followed by bleeding or by ovulation, in which case it activates a thermal shift and a "true" period. These first "true periods" are often the first ones to be accompanied by pain. Luteal phase activity is less than in an adult (absence or insufficiency of progesterone secretion) and this effects cycle-length, variations in length and frequency of periods and even pain and the volume of blood lost. The first year sees the greatest irregularity, with cycles lasting anything from 15 days to several months [long cycles (>35 days) being more frequent than short cycles (>25days)]. Half of the "cycles" are anovulatory, and periods are often long and heavy. Dysmennhorea often begins during this first year, highlighting the first ovulations. The cycles shorten in the following 3 to 5 years, and ovulation gradually becomes established. Ultrasound scans reveal that the ovaries of adolescents are greater in volume than the adult ovary (6 cm3) and their echostructure is multi-follicular. Then as the cycles become ovulatory, the volume diminishes and the echostructure becomes homogenous. Menstrual anomalies are thus very frequent during adolescence, and are mostly functional and transitory. But it is important not to ignore those rare organic etiologies which pose diagnostic and therapeutic problems. ( Thibaud E et al, 1998, Sultan C et al, 1998)
HOW TO DEAL WITH HEAVY BLOODLOSS IN ADOLESCENT GIRLS
TO UNDERSTAND
TO ADVISE
These episodes of bleeding are abnormal by their abundance, length or frequency: they are not cyclical. They are functional in 80% of cases: their cause is anovulation. The period results from the successive and then simultaneous action of oestrogens and progesterone, then their withdrawal. When there is an unsuccessful attempt at ovulation, the oestrogen level rises and causes the endometrium to thicken, but in the absence of ovulation, the oestrogen drops to its base level, and the endometrium, deprived of hormones bleeds. These fruitless attempts can be repeated. These bleedings are not preceded by a thermal shift but can follow a period of mucus secretion. Other cases may be caused by certain anomalies of haemostasis, eg ~Willebrand's Syndrome and idiopathic thrombopathies, generally known about since early childhood except in crude form and rare organic causes (tumors, complications of pregnancy or contraception, infections).
Explain to the adolescent the physiology of the menarche and the probable functional origin of her trouble. Taking into consideration both clinical assessment and her actual life, discuss with her the alternatives of hormonal treatment or doing nothing.
TO PRESCRIBE Diagnosis is essentially clinical observation, with gynaecological examination and pelvis ultrasonography being necessary if an organic cause is suspected. A ????????????? can be useful but hormonal treatment is not helpful. Emergency treatment for a serious functional haemorrhage involving acute anaemia requires urgent hospitalisation and administration of ?????????????????????? Following an acute incident or in less serious cases, the treatment remains: • either the administration of a ??????????? 10 days from the first raised temperature of the thermal shift or from 16th to 25th day of the “cycle”, in the absence of ovulation • or ??????????????????
PUBERTY DONE 50 HOW TO DEAL WITH LONG CYCLES IN ADOLESCENT GIRLS
TO ADVISE
TO UNDERSTAND The alternating rhythm of oetrogenic and progestogenic phases ensures an alternating rhythm in the development and reduction of oestrogen recepteurs in the target organs. The loss of this rhythm is inclined to maintain abnormally high levels of these oestrogen recepteurs and therefore a greater sensitivity to this hormone The risks resulting from long cycles over a prolonged period of time are found at two levels : - prolonged relative hyperestrogenia is a factor which significantly increases the risk of breast cancer - can lead gradually to the syndrome of polycystic ovaries (Lansac J et al, 2002)
If her periods began less than two years ago and there are no abnormal clinical signs – no examination is needed The doctor can reassure the young girl, explaining to her the way cycles start and why it is quite normal for her cycle to be long at this age. If her periods have been occurring for over two years, it is appropriate to do an assessment of the situation. (Thibaud E et al, 1998)
TO PRESCRIBE After two years, if there are no clinical signs of hyperandrogenia, it is appropriate to : - keep a temperature chart - measure the levels of cirulating FSH, LH, prolactin, testosterone, androstenedione, estradiol, 17 OH progestérone - take pelvic scans to check the volume of the ovaries and their échostructure
No evidence of clinical or biological hyperandrogénie. FSH/LH normal, estradiol variable Progesterone levels low or non existent
No clinical signs of hyperandrogénie
Clinical signs of hyperandrogénie
Hyperandrogenia biologique Testosterone, Androstenedione Raised in variable manner, unstable, LH possibly dissociée
Hyperprolactinaemia
17 OH progestérone raised
Scan : multiple follicles or polycystic (difficult for the many outline shapes)
IRM à la recherche d’un microadénome à prolactine. +/- test au TRH
Insuffisances ovariennes primitives incomplètes congénitales (rares) ou acquises: FSH raised estradiol giving evidence of residual follicular activity
Evolution dans le temps +/- test LH-RH Spanioménorrhée isolée fonctionnelle transitoire (sometimes : involvement of stress, intense sporting activity, eating habits
Hyperandrogénie ovarienne fonctionnelle transitoire
No clinical signs
In relation to the patient’s wish to have « normal » cycles, a course of progestatifs can be offered
If symptoms are persistent and prolonged, progestogen treatment to limit the risks of cancer may be appropriate.
Polycystic ovary Syndrome
Hyperplasie congénitale des surrénales
Clinical signs present
Essai des progestatifs
Treatment with acétate de ciprotérone and estradiol (Thibaud E et al, 1998, Potier A, 1998)
Echec
PUBERTY DONE
51
DEALING WITH DYSMÉNORRHOEA IN ADOLESCENT GIRLS
TO UNDERSTAND
TO ADVISE
This term applies to pelvic pain accompanying the menstruation. Dysménorrhoea can be secondary of local origin : endométriosis, ovarian cyst, utéro-vaginal malformation; but in the majority of cases it is primary and related to an anomaly prostaglandin secretion. The pelvic pain of endometriosis is distinguished from dysmenorrhoea by its apprearance 2 or 3 days before the menstruation. It rarely occurs on the first menstruations, but after a few cycles which were painless. In fact, the first blood losses are usually « bleeds », that is they are not preceded by ovulation and so there is no imprégnation progestéronique and the blood flow is painless. Primary dysménorrhoea cannot occur in a cycle without ovulation, that is, without there being a secretory membrane in the endometrium and myomètre stimulated by secretions from the luteal gland. Generally speaking, there are few cases of real dysménorrhoea after the first pregnancy, whether the delivery is par voie basse or bycaesarian. (Blanc B et al, 1998 ; Lansac J et al, 2002)
Before prescribing anything, the young girl must be told and reassured about the common and benign nature of her condition, that it confirms that her ovaries are working well (if the menstruations were not painful at first, it was probably due to ovulation not occurring). Explain the mechanism of menstruation and take the drama out of a situation which has often been exaggerated by family and friends
TO PRESCRIBE To start with, antispasmodic and analgesic preparations can be prescribed. If they don’t work, treatment with anti-prostaglandins is effective provided it is started before the menstruation arrives. Where the treatment is stopped (10 à 20 % des cas) or where contraception is sought, associé estroprogestatifs are sometimes offered. The progestatifs can also be presribed in the post-ovulatory phase. (Lansac J et al, 2002)
DEALING WITH WHITE DISCHARGE IN ADOLESCENT GIRLS
TO UNDERSTAND Most times it proves to be the secretion of cervical mucus In the cycles of adoscent girls, the latent phase can be interrupted with one or more attempts at ovulation which are unsuccessful. This is caused by simple fluctuations in oestrogen levels or by the launching of a follicle whicch will not go « all the way » but stops for causes unknown or is blocked by stress which is not even serious. These cycles are recognised by repetated patches of mucus discharge interspaced by dry phases. These episodes of mucus are sometimes followed by bleeding, caused by the sharp drop in oestrogen levels, sometimes with a thermal shift and a proper menstruation when ovulation has occurred. (Verschelde P, 1984)
TO PRESCRIBE
TO ADVISE
A modified treatment, if this white secretion proves not to be a cervical mucus secretion or vaginal desquamation (cf. chapter on mucus).
Reassure the girl and her parents when it is simply cervical mucus.
VARIATIONS IN CYCLES DURING A WOMAN’S LIFE
52
POST PARTUM, ALLAITEMENT - DONE
Follicular dévelopment
Atrésie
Delivery lochia
1st
1 occurrence Follicular dévelopment e
Breastfeeding 1- Return of menses without ovulation - The bleeding is infact an early atrésie of a pre-ovulatory follicle - The follicular development has been interrupted
Ovulation Atrésie
Corpus luteum jaune
2st
1 occurrence 2- Return of menses with ovulation
Follicular development
Atrésie
- the bleeding is indeed a menstruation, - development of a follicle took place
Accouchement
1st
1 occurrence
lochies
Follicular development
Ovulation Atrésie
Corpus luteum
latent
WITHOUT BREASTFEEDING
menses mucus temperature bleeding
2(Frey R et al, 1988)
The term « 1st occurrencet » represents the 1st significant event during the post partum phase and can be : - perhaps a bleed as illustrated in fig. 1, where the menstruation returns without ovulation - or it may be a thermal shift preceding the return of menses, but this time with ovulation as in fig. 2
st
1 occurrence
TO INTERPRET
53 (d’après Ecochard R, 1982) Post partum: This is the time between the birth of the baby and the return of “standard” cycles, whether there is breastfeeding or not, and the type of breastfeeding. The birth represents the end of a cycle, with fertilisation and normal development of pregnancy; the post ovulatory phase lasted 9 months. In this way the birth launches a new cycle which will be considerably affected by the pregnancy which has just ended, and also by breastfeeding, if it takes place. Added to that is the personal factor, with each woman having her own reaction to circumstances that affect the return of fertility after delivery. After delivery, the locchia continues for several weeks, followed by a latent phase, a waiting time, which will last a certain length of time, depending on whether a woman breastfeeds or not; then the menses return, defined as the first significant bleeding which requires sanitary protection and occurs at least 10 days after the end of the locchia. The first 5 or 6 cycles will often present some anomalies, such as bleeds, short post ovulatory phases. Finally the cycles return to a pattern similar to what they were before the pregnancy. Yet this evolution occurs in a continuous momentum with improvement being seen from one cycle to the next. dans ces deux cas, le développement folliculaire a bien eu lieu. The first ovulation can occur before or after the return of meses. If it comes before and is preceded by a thermal shift, this constitutes a true menstruation If it comes after, the blood loss is simply a bleeding resulting from premature atresy of a pre-ovulatory follicle In both these cases, follicular development took place. The prolonged latent phase which precedes this first peri-ovulatory phase often includes unsuccessful attempts at ovulation indicated by the appearance of cervical mucus amid an otherwise dry pattern up to that point. During breastfeeding, these attempts at ovulation are often due to a reduction in the suckling period. This latent phase can also be interrupted by patches of bleeding
POUR CONSEILLER
TO UNDERSTAND In the post partum phase without breastfeeding taking place, the arrival of the first “event”, whether a thermal shift or blood loss, may be achieved in several successive waves; starting from the delivery with underdeveloped follicles of 1 – 2 mm (stage 3 or 4) spontaneous progression occurs to the growth of follicles of 2 – 5 mm. (stage 5), and then under the rd influence of FSH, around the 3 week post partum progress is made to larger follicles. The majority of women will end up th th with a stage 8 (pre-ovulatory) follicle and will ovulate around the 40 – 50 day post partum, in accordance with the progress from a class 5 follicle to a class 8. Other women however, despite having the same pattern of follicular development, will experience a sharp atresie leading to a bleeding at the same date. Others again will present with the same follicular development with a less dramatic atresie which does not result in blood loss; follicular development starts again and ovulation follows 15 – 20 days later; this phenomenon can be reproduced several times before finally culminating in ovulation. These waves of development and atresie can be translated in to clinical signs of waves of mucus patches appearing and disappearing at the vulva during the post partum phase, despite consistent breastfeeding.
How to use the Lactational Ammenhorroea Method (LAM): Questions to ask the mother. Is your baby less than 6 months old?
(Labbok MH et al, 1994) NON
OUI
Are you still amenhorroeic (no menstrual flow after the th 56 day after delivery)? NON OUI
The “non result” of follicular development from its very first attempt is most likely due to circumstances in the hypothalamicpituitary-ovarian axis; as regards the ovary, a latent phase is necessary (40 days in the usual cycle) for a follicle to pass from stage 3 to stage 4; as for the hypothalamus, a latent phase is needed before de retrouver…. (Frey R et al, 1988) In the post partum phase with breastfeeding With delivery, a rapid fall in the placental hormones is seen in the mother. If the nipple or aureola receives no stimulation, the prolactin levels fall rapidly and this produces a return to the normal ovarian hormonal cycle within 6 to 12 weeks following delivery. On the other hand, if the nipple is sufficiently stimulated after the delivery, the level of prolactin is persistently elevated. As long as lactation is intensive, the ovarian hormones are suppressed for a time following delivery. This interaction is achieved by the intermediary of a complex feedback mechanism of the hypothalamic-pituitary-ovarian axis. The conditions needed to maintain this feedback mechanism can be summarised as follows: the breastfeeds must be frequent, without too long intervals, and no other supplements or bottles must be given to the baby. These conditions maximise the stimulation of the nipple, a signal is sent to the hypothalamus resulting in a truchement…., hormone production is blocked which prevents the return of ovulation. It must be noted that the further away from the delivery, the more frequent is the incident of ovulation before any bleeding. (Labbok MH et al, 1989) . It has also been observed that “the number of breastfeeds during the 24 hour period” is the most critical factor for maintaining prolonged post partum infertility. There are variations in sensitivity between one woman and another clearly seen with regard to ovulation returning or not returning even though they were delivered at exactly on exactly the same day and seemed to follow very similar breastfeeding patterns. (Coste MO, 1986)
Are you fully/ or nearly fully breastfeeding your baby
The possibility of pregnancy increases. If the woman wishes to avoid conception, she should use another method of FP but continue to BF her baby
NON
OUI
THE PREGNANCY RATE IS LESS THAN 2% Tell the mother that when the answer to any of these questions is NO * the light bleedings that occur within the first 56 are not considered as menstruations
POUR EN SAVOIR PLUS After the return of menses without ovulation, there is more disturbance and delay of ovulation in the two following cycles compared with a return to menses preceded by a thermal shift. .(Frey R et al, 1989)
VARIATIONS IN CYCLES DURING A WOMAN’S LIFE
54
POST-PILL - DONE
Chart 1a- first cycle after stopping the pill
Chart1b- continuation of first cycle (after bleeding)
Charte 1c- continuation of first cycle (after another episode of bleeding) leedingsaignement)
Cycles of a woman 32 years old with 3 children (the last one 3 years old) ; 12 months on the pill, in two episodes (discontinued due to migraine). Chart 2- second cycle post pill
Chart 3- third cycle post pill first high reading
red loss
Abondant red loss
Chart4a- fourth cycle post pill
Chart 4b- continuation of fourth cycle (after bleeding)
POUR INTERPRETER The disturbances most often seen following the pill are: Long cycles (more than 35 days in length)
Short luteal phases (less than 10 days)
POUR COMPRENDRE
latent menses glaire temperature bleeding
Absence of ovulation
Disturbed pattern of cervical mucus secretion
Short episodes of mucus ( 2 days), particularly frequent in the first 3 cycles.
The cervix sometimes (less often) abnormally dry; the temperature chart can identify a thermal shift even when the vaginal discharge is defective in quality (thick mucus) or quantity (a little mucus is felt but nothing or very little seen externally) or it is short in duration. Note that vaginal discharge can interfere with mucus observation post pill phase: candida (which can be directly linked to taking the pill) …. (de la Salle V, 1987 ; Odeblad E, 1992)
POUR CONSEILLER Le retour The return of normal cycles does not happen in quick succession as in the post partum phase. It is important to explain this to the woman to overcome her anxiety. In fact the decision to stop the pill is often motivated by a desire to have a baby and it is important to reassure the woman who is confused and sometimes feels guilty about the disturbances to her cycles. Taking into account the possible delay in the return of normality , it is wise to encourage a couple wanting to conceive to concentrate only on mucus observation.
55
The disturbances to cycles after stopping the contraceptive pill are reversible but the restoration of the normal function of the hypothalamic-pituitary-ovarian cycle takes up to 9 months or more. Several hypotheses have been advanced to explain the causes of disturbances to the cycles post pill: Insufficient maturation of the follicle (due to insufficient FSH response perhaps to itself an abnormal pulsatility of RH-LH): the high percentage of deficient luteal phases is the result of a disturbance in the maturation of the follicle which is more frequent in the first seven months post pill. The blockage to the hypothalamic-pituitary axis – will it be lifted gradually? On peut In the same way, the alteration of fertility post pill is explained in certain cases by: Hyperprolactinaemia Ovarian dystrophy Failure of the hypothalamus to trigger the cycles Alteration of the secretory epithelium of the cervical canal, the cervix producing hardly any mucus Pathological situations post pill are not uncommon and prolonged disturbance of cycles should be investigated for: Hyperprolactinaemia, which can be responsible for anomalies in extremely long cycles and is sometimes accompanied by galactorrhoea, spontaneous or provoked, an erratic sign but Polycystic ovarian syndrome A complete arrest of follicular development, secondary to the absence of a pulsatile secretion of LH and FSH due to an absence of stimulation from the hypothalamus . (d’après Ecochard R, 1992)
POUR EN SAVOIR PLUS The prospective study in Germany by the team of Freundl continuing for 15 years now has compared 3048 cycles charted by 175 women immediately after stopping the contraceptive pill with 6251 cycles charted by 284 women who had never taken the contraceptive pill. These two groups were comparable in terms of age and socio-demographic structure After stopping the pill, 68% of cycles were ovulatory with a luteal phase sufficient in length. In the post pill group, cycle length was significantly increased and up to the 9th cycle. A significantly greater number of luteal phases were deemed to deficient. The main disturbances were significantly more common in the post pill group, lasting up to 7th cycle : 22.9% of the first cycles post pill were >35 days , compared to 8,10% in the control group, and the difference is significant for 2nd and 3rd cycles post pill as well. 31.86% of cycles post pill had a luteal phase < 10 compared with 18.69% in the control group and the difference was also significant for 2nd cycle post pill. 10.24% of first “cycles” were monophasic (in the control group 3.44% monophasic), and the difference is also significant for 2nd and 3rd cycles post pill. Le taux d’aménorrhée prolongée post-pilule est de 1,71%.
The start of the mucus de mucus is not different within the two cohorts, but the peak day occurred on average on the 23,19th day +/_ 16,99 (medien +/_ déviation standard) in the first cycle post pill and on the 18,09 +/_ 5,07 in the first cycle of the control group. The length of the follicular phase (defined as the first day of menses until the first day of temperature rise) is significantly longer and continues so until the 7th cycle after stopping the pill The lengthening of the cycle takes place most commonly in the follicular phase (statistically significant up to 8th cycle post-pilule) with the luteal phase of normal length although it can be slightly or significantly shorter (until 9th cycle). This study did not permit any direct conclusion as to diminution of fertility after stopping the contraceptive pill. It showed that anomalies recognised to be associated with lower probability rate of conception (cycles >35 jours, phase lutéale
